Hepatitis C virus (HCV) has infected about 180 million people worldwide. HCV infected patients suffer from acute hepatitis, part of whom is completely cured, but most of whom (50 to 80%) develop chronic hepatitis. It is known that about 20% of chronic hepatitis patients develop liver cirrhosis or liver cancer.
At present, as there is no commercialized vaccine against HCV, the medical approach to prevention thereof is impossible. As the standard-of-care treatment for HCV, a combination therapy of PEG-IFN-α and ribavirin, a nucleoside analogue, is used. However, there may be side effects including flu like symptoms (fever, fatigue, muscular pain, headache, chill, etc.), anemia, neutropenia, thrombocytopenia, increase in serum ALT, neuropsychiatric disorders, thyroid dysfunction, respiratory diseases (interstitial pneumonia, etc.), ocular disorders (retinal hemorrhage, loss of color sense, etc.), skin diseases (erythema, rash, etc.), hair loss, etc.
Also, the standard-of-care treatment for HCV exhibits limited effects depending on HCV genotypes. A sustained virological response (SVR; absence of detectable HCV in serum for 6 months after stopping therapy) reached about 80% for genotypes 2 and 3, whereas a SVR reached less than 50% for genotypes 1 and 4, which means that the likelihood of recurrence is high.
Recently, in order to overcome the limited effect of the combination therapy of PEGylated interferon and ribavirin, drugs of direct-acting antivirals (DAA) have been developed. Telaprevir and boceprevir have been approved and used as HCV NS3-NS4A protease inhibitors. However, these drugs are also known to show limited effect for genotype 1b, and drug resistance is a matter of concern.
Therefore, it is urgent to develop anti-HCV drugs which can be used to patients on whom the standard-of-care treatment for HCV does not work and are applicable with no limitation to genotypes.
Meanwhile, GRIM19, a cell death-associated gene, is currently known as a partner interacting with STAT3 through yeast-2-hybrid screening (Zhang J, Yang J, Roy S K, Tininini S, Hu J, Bromberg J F. et al. Proc Natl Acad Sci USA. 2003; 100:9342-9347). GRIM19 is also known to inhibit STAT3-mediated transcription without inhibiting phosphorylation of tyrosine and serine residues or blocking its binding to DNA (Chung C D, Liao J, Liu B, Rao X, Jay P, Berta P. et al. Science. 1997; 278:1803-1805). However, there is no report on GRIM19 in relation with hepatitis C virus.
Under such background, the present inventors confirmed that the expression of GRIM19 was reduced in liver tissues of patients with chronic liver disease caused by HCV and cells infected with HCV. Also, the present inventors confirmed that GRIM19 overexpression has an effect of inhibiting HCV replication. Thereby, the present inventors completed the present invention.